Noninvasive, nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of a variety of living subjects including experimental animals, normal humans and patients. These techniques rely on the use of sophisticated imaging instrumentation that is capable of detecting radiation emitted from radiotracers administered to such living subjects. The information obtained can be reconstructed to provide planar and tomographic images that reveal distribution of the radiotracer as a function of time. Use of appropriately designed radiotracers can result in images which contain information on the structure, function and most importantly, the physiology and biochemistry of the subject. Much of this information cannot be obtained by other means. The radiotracers used in these studies are designed to have defined behaviors in vivo which permit the determination of specific information concerning the physiology or biochemistry of the the subject or the effects that various diseases or drugs have on the physiology or biochemistry of the subject. Currently, radiotracers are available for obtaining useful information concerning such things as cardiac function, myocardial blood flow, lung perfusion, liver function, brain blood flow, regional brain glucose and oxygen metabolism.
Compounds can be labeled with either positron or gamma emitting radionuclides. For imaging, the most commonly used positron emitting (PET) radionuclides are 11C, 18F, 15O and 13N, all of which are accelerator produced, and have half lifes of 20, 110, 2 and 10 minutes, respectively. Since the half-lives of these radionuclides are so short, it is only feasible to use them at institutions that have an accelerator on site or very close by for their production, thus limiting their use. Several gamma emitting radiotracers are available which can be used by essentially any hospital in the U.S. and in most hospitals worldwide. The most widely used of these are 99mTc, 201T1 and 123I.
In the two decades, one of the most active areas of nuclear medicine research has been the development of receptor imaging radiotracers. These tracers bind with high affinity and specificity to selective receptors and neuroreceptors. Successful examples include radiotracers for imaging the following receptor systems: estrogen, muscarinic, dopamine D1 and D2, opiate, neuropeptide-Y, and neurokinin-1.
The natural ligands for the cannabinoid receptors are termed endogenous cannabinoids (endocannabinoids) and include arachidonoyl ethanolamide (anandamide), 2-aminoethyl arachidonate (virodhamine), 2-arachidonoyl glycerol, and 2-arachidonoyl glyceryl ether (noladin ether). Each is an agonist with activities similar to Δ9-tetrahydrocannabinol, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation. There are two known receptor subtypes for cannabinoids, designated CB1 and CB2. The CB1 receptor subtype is widely distributed throughout the mammalian nervous system (especially brain), and certain peripheral tissues (including the pituitary gland, immune cells, reproductive tissues, gastrointestinal tissues, superior cervical ganglion, heart, lung, urinary bladder, and adrenal gland). The CB2 receptor subtype is present mainly in immune cells (especially B-cells and natural killer cells). A common role for both cannabinoid receptor subtypes is the modulation of the neuronal release of chemical messengers, including acetylcholine, noradrenaline, dopamine, serotonin, γ-aminobutyric acid, glutamate, and aspartate. The receptors for cannabinoids are members of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions.
As noted in the review by Gifford A N, et al., (In Vivo Imaging of the Brain Cannabinoid Receptor, Chemistry and Physics of Lipids, 2002, 121 (1-2), 65-72), “Although rodent studies have indicated that in vivo imaging of CB1 receptors is feasible, at the present time this receptor has still to be successfully imaged in a human PET study.” (Id., p. 65.). CB1 receptor radioligands for imaging brain CB1 receptors have been made, but in humans have been limited either by poor signal-to noise ratios, low brain uptake and/or rapid clearance. Other attempts are detailed in the following: Lan R, et al., Preparation of Iodine-123 Labeled AM251: A Potential SPECT Radioligand for the Brain Cannabinoid CB1 Receptor, J Labelled Cmpd Radiopharm, 1996, 38(10), 875-881. ([123I]-labeling of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, an analog of SR131716A (rimomabant)); Gatley S J, et al., Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo, J Neurochemistry, 1998, 70(1), 417-423. ([123I]AM281 studies in mice and baboons); Mathews W B, et al., Synthesis of [18F]SR144385: A Selective Radioligand for Positron Emission Tomographic Studies of Brain Cannabinoid Receptors. J Labelled Cmpd Radiopharm, 1999, 42, 589-596; Mathews W B, et al., Biodistribution of [18F]SR144385 and [18F]SR147963: Selective Radioligands for Positron Emission Tomographic Studies of Brain Cannabinoid Receptors. Nuc Med Biol, 2000, 27, 757-762. (synthesis of two pyrazole PET ligands and the results of PET experiments with these ligands in mice); Mathews W B, et al., Carbon-11 Labelled Radioligands for Imaging Brain Cannabinoid Receptors, Nuc Med Biol, 2002, 29, 671-677 (synthesis of [11C] SR149080 and [11C]SR149568 two 4-methoxy analogs of rimombabant, and in vivo evaluation in mice); Katoch-Rouse R, Horti A G. Synthesis of N-(piperidin-1-yl)-5-(4-methoxypheny)-1-(2-chlorophenyl)-4-[18F]fluoro-1H-pyrazole-3-carboxamide by nucleophilic [18F] fluorination: a PET Radiotracer for Studying CB1 Cannabinoid Receptors, J Labelled Cmpd Radiopharm, 2003, 46, 93-98 (synthesis); Katoch-Rouse, R, et al., Synthesis, Structure-Activity Relationship and Evaluation of SR141716 Analogues: Development of Central Cannabinoid Receptor Ligands with Lower Lipophilicity, J. Med. Chem., 2003, 46, 642-645; Willis P G, et al., Regioselective F-18 Radiolabeling of AM694, A CB1 Cannabinoid Receptor Ligand, J Labelled Cmpd Radiopharm, 2003, 46, 799-804. (synthesis of [1-(5-[18F]fluoroopentyl)-1H-indol-3-yl]-(2-iodophenyl)methanone); Kumar et al., Synthesis of [O-methyl-11C]1-2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide: a potential PET ligand for CB1 receptors, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 2393-2396; and Berding et al., [123I]AM281 Single-Photon Emission Computed Tomography Imagining of Central Cannabinoid CB1 Receptors Before and After delta9-Tetrahydrocannabinal Therapy and Whole-Body Scanning for assessment of Radiation Dose in Tourette Patients, Biol Psychiatry, 2004, 55, 904-915.
Excessive exposure to Δ9-THC can lead to overeating, psychosis, hypothermia, memory loss, and sedation. Specific synthetic ligands for the cannabinoid receptors have been developed and have aided in the characterization of the cannabinoid receptors: CP55,940 (J. Pharmacol. Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther. 1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; Life Sci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999, 288, 582-589). The pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents 1998, 8, 301-313; Ann. Rep. Med. Chem, A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538; Trends in Pharma. Sci. 2000, 21, 218-224).
Cannabinoid receptor modulating compounds are disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837, 5,081,122, and 5,112,820, 5,292,736 5,532,237, 5,624,941, 6,028,084, and 6,509,367, 6,355,631, 6,479,479 and in PCT Publications WO96/33159, WO97/29079, WO98/31227, WO 98/33765, WO98/37061, WO98/41519, WO98/43635 and WO98/43636, WO99/02499, WO00/10967, and WO00/10968, WO 01/09120, WO 01/70700, WO 01/96330, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 02/076949, WO 03/066007, WO 03/007887, WO 03/02017, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/037332 and WO 03/040107, and EP-658546.
Schultz, E. M, et al. J. Med Chem. 1967, 10, 717 and Pines, S. H. et al. J. Med. Chem. 1967, 10, 725 disclose maleamic acids affecting plasma cholesterol and penicillin excretion.
PET (Positron Emission Tomography) radiotracers and imaging technology may provide a powerful method for clinical evaluation and dose selection of cannabinoid-1 receptor agonists, inverse agonists, and antagonists. Using a fluorine-18 or carbon-11 labeled radiotracer that provides a cannabinoid-1 receptor-specific image in the brain and other tissues, the dose required to saturate cannabinoid-1 receptors can be determined by the blockade of the PET radiotracer image in humans. The rationale for this approach is as follows: efficacy of a cannabinoid-1 receptor modulator is a consequence of the extent of receptor inhibition, which in turn is a function of the degree of drug-receptor occupancy.
It is, therefore, an object of this invention to develop radiolabeled cannabinoid-1 receptor modulator that would be useful not only in traditional exploratory and diagnostic imaging applications, but would also be useful in assays, both in vitro and in vivo, for labeling the cannabinoid-1 receptor and for competing with unlabeled cannabinoid-1 receptor antagonists, inverse agonists, and agonists. It is a further object of this invention to develop novel assays which comprise such radiolabeled compounds. It is yet a further object of the present invention to develop intermediates for the synthesis of radiolabled cannabinoid-1 modulators.